WO2019065792A1 - Cristaux - Google Patents

Cristaux Download PDF

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Publication number
WO2019065792A1
WO2019065792A1 PCT/JP2018/035828 JP2018035828W WO2019065792A1 WO 2019065792 A1 WO2019065792 A1 WO 2019065792A1 JP 2018035828 W JP2018035828 W JP 2018035828W WO 2019065792 A1 WO2019065792 A1 WO 2019065792A1
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WO
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Prior art keywords
degrees
crystal
butyloxy
isopropylamino
diphenylpyrazin
Prior art date
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PCT/JP2018/035828
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English (en)
Japanese (ja)
Inventor
聡夫 冨士原
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日本新薬株式会社
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Publication date
Priority to JP2019545594A priority Critical patent/JP7160043B2/ja
Priority to KR1020247009414A priority patent/KR20240042215A/ko
Priority to SG11202002443QA priority patent/SG11202002443QA/en
Priority to US16/650,390 priority patent/US10906879B2/en
Priority to KR1020207008812A priority patent/KR20200060393A/ko
Priority to EP18860498.7A priority patent/EP3689854A4/fr
Priority to AU2018338856A priority patent/AU2018338856B2/en
Priority to UAA202002567A priority patent/UA126928C2/uk
Priority to BR112020005428-3A priority patent/BR112020005428A2/pt
Priority to RU2020112117A priority patent/RU2020112117A/ru
Priority to CA3076877A priority patent/CA3076877A1/fr
Priority to MX2020007315A priority patent/MX2020007315A/es
Priority to CN202311466995.6A priority patent/CN117510418A/zh
Priority to CN201880063158.XA priority patent/CN111263754A/zh
Application filed by 日本新薬株式会社 filed Critical 日本新薬株式会社
Publication of WO2019065792A1 publication Critical patent/WO2019065792A1/fr
Priority to IL273430A priority patent/IL273430A/en
Priority to CONC2020/0003424A priority patent/CO2020003424A2/es
Priority to PH12020550149A priority patent/PH12020550149A1/en
Priority to US17/134,796 priority patent/US11655218B2/en
Priority to JP2022154085A priority patent/JP7485738B2/ja
Priority to US18/133,666 priority patent/US20230303500A1/en
Priority to AU2023274142A priority patent/AU2023274142A1/en
Priority to JP2024024462A priority patent/JP2024045685A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel crystal of 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ acetic acid (hereinafter referred to as "compound B").
  • the compound to be the active ingredient is required to have high physical and chemical stability.
  • it is general to adopt a crystal which can be expected to have high stability.
  • the process of screening crystals of the active ingredient of a pharmaceutical not only is it difficult to find the optimum conditions for obtaining crystals, but even when crystals are obtained, the presence of crystal polymorphism is often a problem Often. The problem is due to the difference in the physicochemical stability depending on the crystal form.
  • the purity may decrease and the crystal form transition may occur depending on the external environment at the time of storage, making it difficult to maintain the compound at a constant quality.
  • the crystal form it may cause unforeseen situations such as reduction of drug efficacy and side effects.
  • the crystal of the compound to be the active ingredient of the pharmaceutical is successfully obtained, it is necessary to strictly evaluate the physicochemical stability of the crystal polymorph.
  • Compound B has excellent PGI 2 receptor agonism, and shows various medicinal effects such as platelet aggregation suppression action, vasodilation action, bronchial muscle dilation action, lipid deposition suppression action, leukocyte activation suppression action, etc.
  • PGI 2 receptor agonism shows various medicinal effects such as platelet aggregation suppression action, vasodilation action, bronchial muscle dilation action, lipid deposition suppression action, leukocyte activation suppression action, etc.
  • the present situation is that it is not known whether the formation of crystals is possible, not only the existence of crystal polymorphs, but the acquisition of optimum crystals is developed as a medicine. It was an important issue on the top.
  • An object of the present invention is to provide a crystal of Compound B excellent in physicochemical stability and to provide a pharmaceutical composition containing the crystal as an active ingredient.
  • Example 42 of Patent Document 1 The method for producing Compound B is disclosed in Example 42 of Patent Document 1.
  • Example 42 of Patent Document 1 it is not clearly indicated what form of Compound B was obtained. Therefore, when the present inventor attempted to produce Compound B by the same procedure as the method disclosed in Example 42 of Patent Document 1, the form is a crystal (hereinafter referred to as "type III crystal"). It turned out (refer the reference example 1 mentioned later).
  • the results of powder X-ray diffraction measurement, IR measurement and DSC measurement of the type III crystal are shown in FIG. 1, FIG. 2 and FIG. 3, respectively.
  • Test Example 1 described later it was found that the type III crystal is thermodynamically unstable. Therefore, as a result of intensive studies to solve the above problems, the inventor of the present invention found that The present invention has been completed by finding that the more stable type I crystals and type II crystals exist.
  • Examples of the present invention include the following (1) to (7).
  • the crystal form I of Compound B (hereinafter referred to as “Compound B”, which shows diffraction peaks at 13.2 degrees, 15.7 degrees, 17.0 degrees, 19.5 degrees, 20.3 degrees, 21.0 degrees and 22.8 degrees "This invention is called Form I crystal”), (2) in an infrared absorption spectrum, wave number 2874cm -1, 1736cm -1, 1558cm -1 , 1375cm -1, the invention I-type crystals exhibiting an absorption peak at 1126cm -1 and 696cm -1, (3) The present invention type I crystal having an endothermic peak at 127 ° C.
  • Compound B which shows diffraction peaks at 17.5 °, 18.5 °, 18.7 °, 19.9 °, 20.1 °, 21.0 ° and 24.6 °
  • This invention's type II crystal (5) in the infrared absorption spectrum, wave number 2867cm -1, 1749cm -1, 1568cm -1 , 1382cm -1, the invention II type crystals exhibiting an absorption peak at 1131cm -1 and 701cm -1, (6)
  • type II crystal having an endothermic peak which is 147 ° C. in differential scanning calorimetry, (7)
  • a pharmaceutical composition comprising the crystal according to any one of (1) to (6) as an active ingredient
  • the obtained value is preferably within the range of the value ⁇ 0.2 degrees, preferably within the range of the values ⁇ 0.1 degrees. It should be understood as inside.
  • the obtained value is within the range of the value ⁇ 2 cm ⁇ 1 .
  • the obtained value is within the range of the value ⁇ 3 ° C.
  • FIG. 1 shows a chart of powder X-ray diffraction spectrum of Form III crystal.
  • the vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 2 shows a chart of the IR spectrum of Form III crystal.
  • the vertical axis represents transmittance (%), and the horizontal axis represents wave number (cm ⁇ 1 ).
  • the chart of the DSC measurement at the time of making temperature rise by 10 ° C a minute for type III crystal is shown.
  • the vertical axis of the figure indicates the calorific value (mW) (in the case of minus, the heat absorption amount), and the horizontal axis indicates the temperature (° C.).
  • the vertical axis represents transmittance (%), and the horizontal axis represents wave number (cm ⁇ 1 ).
  • BRIEF DESCRIPTION OF THE DRAWINGS The chart of IR spectrum of this invention type II crystal is shown. The vertical axis represents transmittance (%), and the horizontal axis represents wave number (cm ⁇ 1 ).
  • BRIEF DESCRIPTION OF THE DRAWINGS The chart of the DSC measurement at the time of making temperature rise by 10 degreeC per minute of this invention type I crystal is shown.
  • the vertical axis indicates the calorific value (mW) per second (in the case of minus, the heat absorption amount), and the horizontal axis indicates the temperature (° C.).
  • the present invention I type crystals in the IR spectrum (KBr method), wave number 2874cm -1, 1736cm -1, 1558cm -1 ,, 1375cm -1, to show an absorption peak at 1126cm -1 and 696cm -1 It features.
  • the crystalline form I of the present invention is characterized by having an endothermic peak at 127 ° C. in differential scanning calorimetry.
  • the present invention type I crystal can be obtained, for example, by the method described in Example 1 described later.
  • the present invention II crystals present invention II type crystals in the powder X-ray diffraction spectrum obtained by using Cu K [alpha radiation (lambda 1.54 ⁇ ), is 9.6 degrees diffraction angle (2 [Theta]), 11.4 degrees, Show diffraction peaks at 11.7 °, 16.3 °, 17.5 °, 18.5 °, 18.7 °, 19.9 °, 20.1 °, 21.0 ° and 24.6 ° It is characterized by Preferably, in addition to the diffraction peak, 19.4 degrees, 20.6 degrees, 21.1 degrees, 21.7 degrees, 22.7 degrees, 26.6 degrees, 26.7 degrees, 28.8 degrees And a diffraction peak at 30.8 degrees.
  • the present invention type II crystal is characterized by showing absorption peaks at wave numbers of 2867 cm -1 , 1749 cm -1 , 1568 cm -1 , 1382 cm -1 , 1131 cm -1 and 701 cm -1 in an IR spectrum (KBr method). I assume.
  • the crystalline form II of the present invention is characterized by having an endothermic peak at 147 ° C. in differential scanning calorimetry.
  • the present invention type II crystal can be obtained, for example, by the method described in Example 2 described later.
  • composition of the present invention has excellent PGI2 receptor agonism, and has platelet aggregation suppression action, vasodilation action, bronchial muscle dilation action, lipid deposition suppression action, leukocyte activation suppression It exhibits various medicinal effects such as action (see, for example, Patent Document 1).
  • the crystal of the present invention type I, the crystal of the present invention type II (hereinafter collectively referred to as "the present crystal") or the pharmaceutical composition of the present invention is a transient ischemic attack (TIA), diabetic neuropathy ( For example, see non-patent document 1), diabetic gangrene (see, for example, non-patent document 1), peripheral circulatory disorder [for example, chronic arterial occlusion (see, for example, non-patent document 2), intermittent claudication (for example, Non-patent document 3), peripheral arterial embolism, vibration disease, Raynaud's disease] (see, for example, non-patent document 4, non-patent document 5), collagen disease [eg, systemic lupus erythematosus, scleroderma (eg, Patent Document 7, Non-patent Document 6), mixed connective tissue disease, vasculitis syndrome], re-occlusion / resstriction after percutaneous coronary angioplasty (PTCA), arteriosclerosis, thrombos
  • crystal of the present invention or the pharmaceutical composition of the present invention is also useful as an accelerator for angiogenesis therapy such as gene therapy or autologous bone marrow cell transplantation, or as an angiogenesis promoter in peripheral revascularization or angiogenesis therapy.
  • the crystal of the present invention When administered as a pharmaceutical, is, for example, in the range of 0.1% to 99.5%, preferably in the range of 0.1% to 99.5% as it is or in a pharmaceutically acceptable non-toxic and inert carrier. It is contained in the range of 5% to 90%.
  • the carrier include solid, semi-solid or liquid diluents, fillers, and other formulation aids. One or more of these can be used.
  • the pharmaceutical composition of the present invention is a solid or liquid dose unit, and an orally administered preparation such as powder, capsule, tablet, dragee, granule, powder, suspension, solution, syrup, elixir, troche and the like. It can take any form of parenteral preparations such as injections and suppositories. It may be a sustained release preparation. Among them, oral dosage formulations such as tablets are particularly preferred. Powders can be prepared by appropriately sizing the crystals of the present invention. Powders can be prepared by mixing the crystals of the invention with appropriate fineness and then grinding with an equally finely divided pharmaceutical carrier, for example, an edible carbohydrate such as starch or mannitol.
  • an edible carbohydrate such as starch or mannitol.
  • Flavoring agents, preservatives, dispersing agents, coloring agents, flavoring agents and the like can be optionally added.
  • the capsule is first produced by filling the powdery powder as described above or the granulated powder as described in the section of powder or tablet into, for example, a capsule shell such as a gelatin capsule. can do.
  • lubricants and fluidizers for example, colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, are mixed with powdered powder or powder, and then the filling operation is performed.
  • Disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, calcium carbonate and sodium carbonate, when the capsule is ingested Can improve the efficacy of
  • the fine powder of the crystal of the present invention may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin and surfactants, and this may be covered with a gelatin sheet to make a soft capsule.
  • Tablets can be prepared by adding excipients to the powdered crystals of the present invention to form a powder mixture, granulating or slugging, and adding a disintegrant or lubricant followed by tableting.
  • Powder mixtures can be prepared by mixing appropriately powdered crystals of the present invention with diluents and bases.
  • a binder eg, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
  • a dissolution delaying agent eg, paraffin
  • a resorbing agent eg, quaternary salt
  • An adsorbent eg, bentonite, kaolin
  • Granules can be produced by first moistening the powder mixture with a binder such as syrup, starch paste, arabica gum, cellulose solution or polymer solution, stirring and mixing, drying and grinding it.
  • a transparent or semi-transparent protective film consisting of a sealing film of shellac, a coating film consisting of a coating of sugar or polymer material and a wax can also be used.
  • Other orally administered formulations, such as solutions, syrups, troches and elixirs, can also be in dosage unit form in which a given amount contains a certain amount of crystals according to the invention.
  • a syrup may be prepared by dissolving the crystals of the present invention in a suitable aqueous flavor solution.
  • Elixirs can be prepared by using non-toxic alcoholic carriers.
  • Suspensions can be prepared by dispersing the crystals of the invention in a non-toxic carrier.
  • solubilizers and emulsifiers for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor imparting agents (for example, peppermint oil, saccharin), etc. may be added. it can.
  • dosage unit formulations for oral administration can be microencapsulated. The formulation can also provide extended action time and sustained release by coating, embedding in polymers, waxes and the like.
  • the parenteral preparation can be in the form of liquid dosage units, for example solutions or suspensions, for subcutaneous, intramuscular or intravenous injection.
  • the parenteral dosage form is prepared by suspending or dissolving a fixed amount of the crystal of the present invention in a nontoxic liquid carrier compatible with the purpose of injection, for example, an aqueous or oily medium, and then sterilizing the suspension or solution. It can be manufactured by carrying out. In addition, stabilizers, preservatives, emulsifiers and the like can be added.
  • the suppository is a solid soluble or insoluble in water, having a low melting point according to the present invention, such as polyethylene glycol, cacao butter, semi-synthetic fat and oil [eg Witepsol (registered trademark)], higher esters (eg palmitic acid) It can be prepared by dissolving or suspending it in myristyl ester) or a mixture thereof.
  • a low melting point such as polyethylene glycol, cacao butter, semi-synthetic fat and oil [eg Witepsol (registered trademark)], higher esters (eg palmitic acid) It can be prepared by dissolving or suspending it in myristyl ester) or a mixture thereof.
  • the amount of the present invention crystal for an adult is 0.001 mg per day.
  • the range of ⁇ 100 mg is suitable, and the range of 0.01 mg ⁇ 10 mg is preferable. In some cases, less than this may be sufficient, and conversely more doses may be required.
  • it can be administered once to several times a day, or at intervals of one day to several days.
  • the powder X-ray diffraction spectrum is SmartLab (manufactured by Rigaku Corporation) (optical system: concentration method, voltage: 45 kV, current: 200 mA, wavelength: Cu K ⁇ , solar slit: 5.0 degrees, scanning range: 4 to 40 degrees) Scanning rate: 47.3 degrees / minute, sample rotation: 60 degrees / minute).
  • the IR spectrum was measured by IR Affinity-1 (manufactured by Shimadzu Corporation) (measurement mode:% Transmittance, number of integrations: 16 times, decomposition: 2.0, wave number range: 400 to 4000 cm ⁇ 1 ).
  • DSC DSC-50 (manufactured by Shimadzu Corporation) (cell: alumina (open), gas: nitrogen (20.0 mL / min), heating rate: 10.0 ° C./min, hold temperature: 250 ° C., hold Time: 0 minutes).
  • Example 1 Preparation of Present Invention Form I Crystalline Compound B (63 g) prepared in Reference Example 2 was dissolved in acetonitrile (315 mL) at 90 ° C., and stirred at the same temperature for 30 minutes. The solution was filtered, washed with 5 mL of acetonitrile and again heated and stirred. After adding a small amount of the compound B prepared in Reference Example 2 as a stimulus, the mixture was gradually cooled and stirred at 10 ° C. or less for 1 hour, then the crystals were filtered and washed with an appropriate amount of acetonitrile. It dried under pressure reduction at 65 degreeC, and obtained 59.5 g of this invention type I crystal
  • Example 2 Preparation of crystal of the present invention type II crystal Compound B (0.5 g) prepared in Reference Example 2 was dissolved in isopropyl alcohol (2.5 mL) and 8% aqueous sodium hydroxide solution (1.5 mL) at 80 ° C. The mixture was stirred at the same temperature for 30 minutes. The reaction solution was gradually cooled to room temperature, adjusted to pH 5 to 6 with 4 N hydrochloric acid aqueous solution at room temperature, stirred at 10 ° C. or less for 1 hour, filtered for crystals, and washed with an appropriate amount of water. It dried under pressure reduction at 65 degreeC, and obtained this invention type II crystal (0.45 g).
  • Test Example 2 Solvent Suspension Test of the Form I Crystal of the Invention in Various Solvents
  • the Form I crystal of the invention was mixed with various solvents and stirred at room temperature for 30 minutes.
  • the formed crystals were collected by filtration to confirm the crystal form.
  • the results are shown in Table 2.
  • the crystals of the present invention type I were partially transferred to the present invention type II crystals under all solvent suspensions. From this result, it was revealed that the crystal of the present invention type II is thermodynamically stable under suspension of various solvents at room temperature.

Abstract

L'invention a pour objet de fournir de nouveaux cristaux d'acide ２－｛４－［Ｎ－（５，６－diphénylpyrazin-2-yl)－Ｎ－ isopropyl‐amino]butyloxy} acétique (ci-après, "composé (B)"). Plus précisément, l'invention concerne des cristaux de type I du composé (B) tels que des angles de diffraction （２θ） présentent des pics aux angles de diffraction de ６,４ degrés, ８,１ degrés, ９,５ degrés, １０,９ degrés, １３,２ degrés, １５,７ degrés, １７,０ degrés, １９．５ degrés, ２０,３ degrés, ２１,０ degrés et ２２,８ degrés, dans un spectre de diffraction des rayons X sur poudre obtenu au moyen d'un rayonnement radioactif Ｃｕ Ｋα（λ＝１,５４Å）. En outre, l'invention concerne des cristaux de type II du composé (B) tels que des angles de diffraction （２θ） présentent des pics aux angles de diffraction ９,６ degrés, １１,４ degrés, １１,７ degrés, １６,３ degrés, １７,５ degrés, １８,５ degrés, １８,７ degrés, １９,９ degrés, ２０,１ degrés, ２１,０ degrés et ２４,６ degrés, dans un spectre de diffraction des rayons X sur poudre obtenu au moyen d'un rayonnement radioactif Ｃｕ Ｋα（λ＝１,５４Å）.
PCT/JP2018/035828 2017-09-28 2018-09-27 Cristaux WO2019065792A1 (fr)

Priority Applications (22)

Application Number Priority Date Filing Date Title
CA3076877A CA3076877A1 (fr) 2017-09-28 2018-09-27 Cristaux
SG11202002443QA SG11202002443QA (en) 2017-09-28 2018-09-27 Crystal
US16/650,390 US10906879B2 (en) 2017-09-28 2018-09-27 Crystalline substituted pyrazines as PGI2 receptor agonists
KR1020207008812A KR20200060393A (ko) 2017-09-28 2018-09-27 결정
EP18860498.7A EP3689854A4 (fr) 2017-09-28 2018-09-27 Cristaux
AU2018338856A AU2018338856B2 (en) 2017-09-28 2018-09-27 Crystal
UAA202002567A UA126928C2 (uk) 2017-09-28 2018-09-27 Кристалічна форма 2-{4-[n-(5,6-дифенілпіразин-2-іл)-n-ізопропіламіно]бутилоксі}оцтової кислоти
BR112020005428-3A BR112020005428A2 (pt) 2017-09-28 2018-09-27 cristal de forma-i, cristal de forma-ii, composição farmacêutica, receptor agonístico pgi2, agente terapêutico compreendendo os referidos cristais e uso dos mesmos
KR1020247009414A KR20240042215A (ko) 2017-09-28 2018-09-27 결정
MX2020007315A MX2020007315A (es) 2017-09-28 2018-09-27 Cristal.
RU2020112117A RU2020112117A (ru) 2017-09-28 2018-09-27 Кристаллическое вещество
JP2019545594A JP7160043B2 (ja) 2017-09-28 2018-09-27 結晶
CN201880063158.XA CN111263754A (zh) 2017-09-28 2018-09-27 结晶
CN202311466995.6A CN117510418A (zh) 2017-09-28 2018-09-27 结晶
IL273430A IL273430A (en) 2017-09-28 2020-03-19 crystal
CONC2020/0003424A CO2020003424A2 (es) 2017-09-28 2020-03-24 Cristal
PH12020550149A PH12020550149A1 (en) 2017-09-28 2020-03-26 Crystal
US17/134,796 US11655218B2 (en) 2017-09-28 2020-12-28 Crystalline substituted pyrazines as PGI2 receptor agonists
JP2022154085A JP7485738B2 (ja) 2017-09-28 2022-09-27 結晶
US18/133,666 US20230303500A1 (en) 2017-09-28 2023-04-12 Crystalline substituted pyrazines as pgi2 receptor agonists
AU2023274142A AU2023274142A1 (en) 2017-09-28 2023-11-29 Crystal
JP2024024462A JP2024045685A (ja) 2017-09-28 2024-02-21 結晶

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WO2021033702A1 (fr) * 2019-08-19 2021-02-25 Nippon Shinyaku Co., Ltd. Sel

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